Process for the preparation of



PROCESS FOR THE PREPARATION OF 1,2,4-

BENZOTHIADIAZINE-LI-DIOXIDES James M. Sprague, Gwynedd Valley, .Pa., assignor-tofi Merck & Co., Inc., Rahway, NJ., a corporation of New Jersey 3 r No Drawing. p

" 3 Claims. ((Il. 2 6tl'2 43o) This invention is concerned with ainovel process for the preparation of 1,2,4-benZothiadiazine-1,ldioxides g' In particulah this invention relates to the preparation of? 1,2,4-benzothiadiazine-l,1 dioxides by reaction}, between- 1 chloral and a disulfamylanilinecompoundhaying at least.

one sulfamyl group in ontho-positiorrto the amino group; It was surprisingly found as a feature of this invention that when chloral is reacted with a disulfamylaniline com- Filed Apr. 1; 1961, s No. 10 1,3321

R is hydrogen or a lower alkyl radical advantageously having from Ho 5 carbon atoms.

While the foregoing structure illustrates a group of compoundswhich can be prepared by the process of this invention, the novel process described herein can be employed to give any desired 1,2,4-benzothiadiaz-ine-l,1-

dioxide compound. V I The process of this invention is morotully described ever, that the examples are illustrative of the various compounds that can be prepared by theprocess ofthis Patented an. 5, 1965 j inthe following examples. It is -tobe understood, how- 3 '10.

invention and of the various conditions under which the i not fto be construed as limiting the invention to the preparation of the particular compounds s pe'cifically de'-" scribed or to the particular conditions employed, it being 1 critical only that the reaction between ;.the disulf-amy lpound of the type described above ii1 the presence of 1a basic catalyst that 'cyclization occursuforming the corresponding 1,2,4-benzothiadiazine-1,l dioxide in high yields.

' withchloral in the presence" of a trace of a weak' base." While it is importantthat chloral be employed in this process, it can'be' used in any of its active forms such as chloral itself or chloral hydrate or chloral alcoholate can be used if desired. i The reaction advantageously is carried out-in the presence of a solvent for the disulfamylaniline compound; dimethylformamide or dimethylacetamide being quite suitable solvents for this purpose.

reaction can be successfully carriedgout; and they'afe aniline and the selected chloral be conducted in the-pres ence of a trace of weak base to provide high yields of the In accordance with the process offthis invention, the 1 selected disul'famylaniline compound is-preferably heated 7 1 Basic conditions are obtained advantageously by adding a trace of any of the conventional weak bases. Potassium fluoride, sodium or potassium hydroxide, tertiary amines and the like have been found to be especially suitable for this purpose.

Following the reaction, the reaction mixture can be worked up in any of the conventionalways to separate the l,2,4-benzothiadiazine-1,1-dioxide compound from the solvent.

The process of this invention has been found to be there especially well suited to the preparation of 1, 2,4-ben-,

"zothiadiazines which contain one sulfamyl substituent attached to the benzenoid ,moiety of the nucleus and which additionally contain at least one other substituent such as a halogen, a halogen-like radical orian alkyl,

desired 1,ZA-beniothiadiaaine-l,l dioxide compounds. EXAMP L'El A -solution .of. 1.4. g. 0.04 mole). of S-chIoro-iA-disuI- famylaniline in, -n1l'of dimethylformamide, 17.6 g.

(0.12 mole) of chloral and 4.6 .g. (0.08 mole) of anhydrous potassium fluoride is heated on the steam bath for 3 hours. Water (100 ml.) is added and the semisolid product is reprecipitated from dilute ammonium hydroxide to give a 76% yield of 6-chloro-7-sulfamyl-1,2,4 benzothiadiazine-1,ldioxide, M.P. 330 C.

EXAMPLE 2 By replacing the 5-chloro-2,4-disulfamylaniline .em-

ployed in Example 1 by an equimolecular quantity of 5- trifluoro-methyl 2,4-disulfamylaniline and following substantially the same procedure described in Example .1

mole) in 50 ml. of dimethylacetarnide, chloral hydrate V (0.02 mole) and a' trace, approximately (0.08 mole), of

, trimethylamine isheated on the steam bath for 5 hours.

alkoxy, nitro or similar radical attached to the benzenoid portion of the nucleus. Substituents lso can be attached to one of the nitrogens in either the 2- or 4-position of the benzothiadiazine nucleus of the products produced by this novel process. The l,2,4-benzothiadiazine-1,1 dioxide compounds prepared by the process of this invention which contain a sulfamyl substituent and at least one other'substituent attached to the benzenoid portion of the structure are useful, inter alia, as diuretic and/or saluretic agents. Among this group of compounds, those possessing an especially high order of effectiveness are compounds having the structure v t alkoxy radical. preferably having 1. to 5 carbonfa'toms or a nitro-group; R is' attached to either the} or 4-position nitrogen *atom and ishydrog'en or. a lower'alkyl,

radical preferably having from 1 to' 5 carbon atoms;.and

Water (100 ml.) is added-and 6 -methyl-7-sulfarnyl-1,2,4- benzothiadiazine-l,l-dioxide is reprecipitated from dilute ammonium hydroxide.

EXAMPLE 4 A solution of S-nitro-2,4 disulfamylaniline in 6 0 ml. of dirnethylformamide, chloral alcoholate (0.12 mole) and a trace of sodium hydroxide (approximately: 0.08 mole) is heated on the steam bath for 3 /2 hours. 'Water (100 ml.) is added and the 6-nitro-7-sulfamyl-1,2,4-benzothiadiazine-1,1-dioxide compound is reprecipitated from dilute ammonium hydroxide.

-EXAM P LES 5 THROUGH 1 By replacing, the 5 chloro-2,4-disulfarnylaniline employed in Example 1 by an equimolecular quantity of one of the following compounds:

7 Ex. No.:

( 5 5-metho xy-2, i-disulfamylaniline,

(6 .5-ch1oro aniline, I (7) S-chloro-Z-(N-methylsulfamyl)-4 sulfarnylaniline,

{ 8 2,4-disulfamylaniline, 1 t, e

.(9) 5 -ch1oro-6-methyl 2,4-disulfamylaniline, .0) 5-fiuoro-2,4-disulfamylaniline,

3 1 1 5-bromo-2,4-disulfamylaniline,

is obtained 6-trifluoromethyl-7-sulfamyl-1,2,4 benzothiadi azine-l,l-dioxide.

g, 2 sulfamyl 4-(N-meth ylsulfamyl) the same procedure described sisting of halogen, lower'allayl, lower alkoxy and intro thiadiaZine-lJ-dioxide, -V a a I (8-) -7;si1lfamyl-l,ZA-benzothiadiazined,l-dioxide, 1

(9) 5-methyl-6-chloro 7 sulfarnyl-l ,2,4-benzothia-" diazinehl-dioxide,

(10) -o-fiuoroqhsulfamyb124 w l t f f fformarnide and a trace amount of potassium fluoride to give fi -trifliioromethyl 7-sulfarnyl-l,2,4 berizothiadiazine- V lJ-dioxid J 7 '7 While the above examples illustrate specific conditions for the preparation of sl,2,4-bezothi-adiazine-l,1dioxide compounds, .it is tobe understood modifications canbe. made in the reaction conditions described in the examples without'jdeparting from the scope of the invent-ionfla'sr l-dioXide, 7'

' 1-1 6-bromo 7 mam;zatamnaaiazm 1,1-dioxide.

defined by the appended claims,

What isjclaimed is? V group and having at least one" additional suh s tituent attached to the benzene ring selected from the group conbenzene rnoiety. 1

,is heated with chloral in the presence of a trace arnount ofbase to give a l,2,4-benzoth iadiazine-1,l-dioxide compound having a sulfarnyl group and at least one additional substituent selected from the group consisting of halogen, lower alkyl, lower alkoxy, and ;nitro attached "to its 2. A process wherein 5'-chloro'-2,4-disulfan1ylaniline is heated with chloral in the presence of dimethylforrnamide and a trace amount of potassiurh fluoride to give -chloro- 7solfamyl-1,2,4-behzdthiadiazine:l,1-dioxide. or 3. A process wherein 5:trifluoromethyl-Z,4-disulfamylaniline isheated with chloral in thepresence of dimethyl- 'Re fje rejric es Cited the'filehf this patent UNITED sTAT sPATENTs OTHER RE ERENCES r V a Novello et al.:' Jour Org. Che'rnistry; vol. 25, pages l. A fiprocess' wherein disulfarnylaniline compounds; 9 -98 7 having one s'ulfamyl group. in ortho-positi0n to the amino Bergman; The Chemistry of l A cetylene" and Related Compounds, page 80,-lnterscience Publishers Inc., N.Y. 

1. A PROCESS WHEREIN DISULFAMYLANILINE COMPOUNDS HAVING ONLY SULFAMYL GROUP IN ORTH-POSITION IN THE AMINO GROUP AND HAVING AT LEAST ONE ADDITIONAL SUBSTITUENT ATTACHED TO THE BENZENE RING SELECTED FROM THE GROUP CONSISTING OF HALOGEN, LOWER ALKYL, LOWER ALKOXY AND NITRO IS HEATED WITH CHLORAL IN THE PRESENCE OF A TRACE AMOUNT OF BASE TO GIVE A 1,2,4-BENZOTHIADIAZINE-1,1-DIOXIDE COMPOUND HAVING A SULFAMYL GROUP AT LEAST ONE ADDITIONAL SUBSTITUENT SELECTED FROM THE GROUP CONSISTING OF HALOGEN, LOWER ALKYL, LOWER ALKOXY, AND NITRO ATTACHED TO ITS BENZENE MOIETY. 